“I have to rely on this life-changing product for treating my disease/medical condition; nothing else works…if only I could rely on its availability every time I need it.” — a patient’s perspective.

Medical and pharmaceutical science has made incredible advances in providing therapies to patients that are transforming quality of life and survival. As a pharmaceutical company, delivering safe, efficacious quality products to patients has always been, and continues to be paramount and what we must strive for. Unfortunately, “drug shortages” have increased in frequency and severity since the early 2000s for many reasons. Though the drivers in Europe and the United States are somewhat different, data suggests that approximately 40–50% of shortages are due to manufacturing quality issues.

A patient’s reality due to a drug shortage underscores the fact that while improving patient care is important, being able to sustain reliable, uninterrupted and timely supply is even more fundamental to patient care. PDA is working with EMA and the U.S. FDA as well as coordinating with other industry associations on ways to reduce drug shortages caused by manufacturing quality issues. PDA is doing this by developing a risk-based approach, having a workshop in September 2014, an upcoming technical report, and several other activities on this topic.
ICH Q9 Quality Risk Management defines harm as “damage to health, including damage that can occur from loss of product quality or availability”. It is simply not enough to focus primarily on manufacturing safe, efficacious products.

As the complexity of supply chains increases, global regulatory expectations continue to evolve, and economic and business motivators introduce more competition, ensuring availability and uninterrupted supply of products, especially medically necessary products that do not have an effective alternative, is a challenge that is drawing higher focus from regulators, legislators, health care providers, manufacturers, and patients.

Until recently, investigation and management of drug shortages was not routine for many health authorities and their primary responsibilities did not extend to the management of supply, or resolving supply shortages. Hence in many ways, legislation and regulatory processes for shortage-related work are under-developed.

Currently there is no harmonized definition for “drug shortage” and alignment is needed on this. Health authorities primarily focus on drug shortages that have patient impact. While not all shortages impact patients, health authorities have an interest in understanding the causes of such issues, “near misses,” and their preventive actions to avoid a similar recurrence. Therefore FDA, EMA and several other Health Authorities are taking the “crisis” situation around drug shortages seriously, and have published various documents on this topic. PDA supports the European Federation of Pharmaceutical Industries and Association’s (EFPIA) description of “a potential drug shortage as the occurrence of internal or external situations (single or in a combination of both) which could result in an interruption of supplies of a medicinal product, if not properly addressed and controlled.”

A Triage: Categorization, patient impact, and end-to-end controls

In the United States, FDA has established a task force on drug shortages and in October 2013, published a Strategic Plan to prevent and mitigate drug shortages. One element of the FDA’s Strategic Plan addresses mitigation improvements. This includes early notification of potential drug shortages so that steps can be taken in collaboration with the FDA to plan, coordinate actions, and reduce supply disruption through measures such as:

• ramping up/activating supply of alternate therapies where available
• expediting inspections and submission reviews for new manufacturing sites, suppliers, and specification changes
• exercising regulatory discretion on controlled importation of similar products approved in other countries
• working closely with manufacturers on quality issues that might lead to supply disruption.

The second element of FDA’s Strategic Plan is focused on preventive strategies such as positive incentives for manufacturing and quality improvements, and use of proactive risk-based approaches for early identification and prevention of manufacturing and quality problems.

In the European Union, EMA has similarly initiated multiple actions such as establishing an internal catalogue of Centrally Authorised Products (CAPs) and nonCAPs, developing a decision tree to assist National Competent Authorities (NCAs) in determining when a coordination of assessment and response is required at the EU level, clarifying reporting requirements for supply restrictions, and establishing a procedure for handling reports of shortages. EMA has also written a couple of draft documents on the topic and reached out to industry associations including PDA to work on proactively avoiding drug shortages. Due to challenges such as parallel trade, different pricing, economic and business environment in different EU countries, decentralized registration procedure, the issue is more complex than in the United States.

Given its importance and criticality, PDA has been actively working on this topic and engaging in dialog with FDA and EMA to find ways to collaborate in driving solutions to the problem of drug shortages. The efforts are aligned with FDA’s Strategic Plan and EMA’s direction on managing drug shortages; they are mainly focused on a science and risk-based approach including how improvements in manufacturing operations and post approval regulatory changes might be implemented in an expedited way.

In 2012, PDA initiated a task force as part of the Paradigm Change in Manufacturing (PCMOSM) project to focus on developing a risk-based approach for prevention and management of drug shortages. This is a continuation of PDA’s Technical Report No. 54 series of documents where a new technical report will be added on “A Risk Based Approach for Preventing and Managing Drug Shortages.” It is important that a Quality Risk Management (QRM) application addresses both proactive prevention of manufacturing quality issues that can potentially lead to drug shortages, and also risk-based actions in the event a shortage were to occur. The TR54 series provides a QRM framework and application case studies to proactively identify, assess and control product quality risks that in combination with supply chain factors might result in a drug shortage. Additionally, Technical Report No. 59: Utilization of Statistical Methods for Production Monitoring supports these risk-based activities using statistical methodologies for quality control and manufacturing shop floor to better understand and monitor a manufacturing process.

PDA’s risk-based approach for prevention of drug shortages emphasizes the importance of looking at end-to-end controls at a product and manufacturing site level, in order to identify potential risks at various stages of the supply chain. Drug supply needs to be managed appropriately based on the medical necessity and criticality of the product in order to prevent shortages (i.e., stock levels, scale and impact of the problem, alternative sources of supply etc.).

The risk-based approach is a 3-step triage model that:

1. Categorizes the criticality of a shortage in terms of patient impact based on product indication and access to alternative therapies
2. Assesses the probability of a shortage occurring based on identification of i) sources for manufacturing quality risks, ii) weak links in the demand to supply process, iii) inventory considerations, and finally
3. Results in decisions on controls to mitigate and manage the risk to both patient safety and product availability

Another element of PDA’s efforts for prevention of drug shortages is related to quality metrics. This work focuses on continuous improvement, early detection of control drifts, and ensuring stable product supply. It includes metrics that assess overall product quality and facility state of control, and metrics to minimize drug shortages.

In October 2013, at EMA’s request, a joint team was established with membership from PDA, ISPE, EFPIA and the European Generic Medicines Association (EGA). The team will collaborate with EMA and NCAs to establish an integrated action plan for managing shortages caused by manufacturing quality issues including baseline measures to show effectiveness in managing drug shortages. This effort will also include communication strategies with Health Authorities in the event of a drug shortage. Each association has ongoing complementary activities on this topic. The joint team will build on and coordinate the unique perspectives and competencies of each organization to address the topic of drug shortages.

PDA is organizing the two-day 2014 Drug Shortage Workshop in September with active engagement from members of FDA’s Drug Shortage Task Force. The workshop will explore application of risk and knowledge management for addressing and preventing drug shortages, incentives for manufacturers to build in proactive controls (such as redundant capacity, new technology, transparency and linkages to supply planning, manufacturing site metrics and quality status for potential manufacturing partners, etc.). The workshop will also discuss technological improvements that can have a positive impact on preventing drug shortages, economic and regulatory barriers to implementation, and potential incentives or regulatory changes that could improve the business case for quality improvements.
The common unifying objective of preventing drug shortages to ensure uninterrupted supply of safe, efficacious products to patients, is bringing regulators, legislators, health care providers and industry together in developing and driving solutions that will serve the best interests of patients and bring patient care to a reliable, sustainable and improved state. It is not an easy challenge to overcome, but a patient’s reality makes this a nonnegotiable. PDA and our volunteer members have a significant role and opportunity in this respect. Join us in this work by commenting on our plans and ideas.

Reference

1. Ramnarine, E., Long, M. & O’Donnell, K. (2013, September). Risk Based Approach to Prevent and Manage Drug Shortages; Presented at 2013 Annual PDA/ FDA Joint Conference, Washington D.C.

About the Authors

Emma Ramnarine is Head of Biologics QC Network at Roche Pharma and is accountable for the biologics QC network strategy.

Stephan Rönninger, PhD, is the Head of External Affairs Europe, International Quality at Amgen (Europe) GmbH.
Anders Vinther is Quality responsible for the Biologics Technical Operations at Roche and Genentech. This includes operational quality leadership for ten biologics sites and for Roche and Genentech’s biologics products.